The human T-cell co-receptor CD4 (Swiss-Prot data bank entry P01730) is the primary target for infection of lymphocytes with the human immunodeficieny viruses HIV-1 and HIV-2. Complex formation between CD4 and the viral envelope glycoprotein gp120 is the primary step which initates the subsequent membrane fusion process (Green, W et al. (2004) The brightening future of HIV therapeutics. Nat Immunol 5, 867-871). The first amino-terminal domain (named Ig-like V-type domain or D1) of altogether four extracellular domains of CD4 plays a predominant role in this process (Kwong, P. D., Wyatt, R., Robinson, J., Sweet, R. W., Sodroski, J. and Hendrickson, W. A. (1998). Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648-659).
Accordingly, inhibitors of this interaction have the potential to prevent or impair the infection with HIV or to prevent and/or treat AIDS (acquired immunodeficiency syndrome). For this reason, antibodies directed against CD4 and having antagonistic properties with respect to the binding of gp120 are presently of high clinical interest. One such antibodies, TNX-355, is currently subject to a phase II clinical trial carried out by Tanox Inc (Reeves, J. D. & Piefer, A. J., Emerging Drug targets for antiretroviral therapy, Drugs, 2005). TNX-355 is a humanized monoclonal antibody that binds to the second extracellular domain of CD4 (called Ig-like C2-type 1 or D2). Entry of HIV into lymphocytes is apparently prevented by inhibiting membrane fusion via a conformational mechanism after association of the CD4 molecule with gp120. According to the product information of Tanox Inc, the antibody was well tolerated in clinical phase I and II trials and showed transient but meaningful loads in HIV-1 infected patients without seeming to impair the normal immune function.
Apart from systemic administration, for example by intravenous injection, such antagonists of the CD4/gp120 interaction should also inhibit the primary event of infection, in particular for migrating CD4 positive immune cells during sexual transmission when topically applied to the vaginal mucosa. Such antagonists are therefore also referred to as “Viral Entry Inhibitors” (see Shattock, R. J. and Moore, J. P. (2003). Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 1, 25-34).
However, antibodies such as TNX-355 may not be suitable for all potential applications. One limiting factor may be their rather large molecular size, which is even the case for their antigen-binding fragments such as Fab fragments. In addition, there is a large effort associated with the biotechnological production of intact antibodies, thus causing high cost of goods.
Accordingly, it would be desirable to obtain alternatives to antibodies that are able to bind the extracellular region of CD4 and to inhibit the interaction with gp120 of HIV, which can be used in pharmaceutical applications as described above. Hence, it is an objective of the present invention to provide such compounds.